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Updated: Sep 11, 2025
Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts
Published on: February 23, 2024
m6A modification of ATG9A regulates ferritinophagy in microglial activation induced by arsenic
Tianxiu Zhou1, Ruiqi Zhou1, Xuejun Jiang2
1Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
Abstract:
Environmental arsenic has been extensively documented to induce neuroinflammation and various neurological disorders. Iron overload has been demonstrated to induce microglial activation, subsequently resulting in neurological dysfunction, while the precise molecular mechanisms remain to be elucidated. In this study, we demonstrated that iron chelation therapy ameliorated arsenic-induced iron overload and microglial activation, which was mediated by ferritinophagy. Upon arsenic exposure, N6-methyladenosine (m6A) modification levels were significantly elevated, corresponding to a reduction in fat mass and obesity-associated protein (FTO). Notably, both systemic and microglial-specific Fto knock-in transgenic mice demonstrated resistance to arsenic-induced microglial activation and neurological dysfunction. Conversely, systemic knock-down and conditional microglial-specific knock-out of Fto exacerbated arsenic-induced microglial activation. Through m6A-sequencing analysis, ATG9A was identified as the predominant m6A-modified autophagy-related gene in arsenic-induced ferritinophagy. The expression of ATG9A was found to be regulated by FTO in an m6A-dependent manner. Importantly, ATG9A knock-down significantly attenuated ferritin degradation in arsenic-treated microglial cells. Human cortical tissues result revealed a positive correlation between arsenic concentration and levels of iron, ATG9A, and inflammatory factors, while FTO and Ferritin levels were inversely correlated with arsenic content. These findings suggest that FTO represents a promising therapeutic target for the amelioration of arsenic-related neurotoxicity .
Insights
Environmental arsenic exposure causes neuroinflammation and neurological disorders. This study reveals FTO protein regulates this process via m6A modification, offering a potential therapeutic target for arsenic neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Environmental arsenic exposure is linked to neuroinflammation and neurological disorders.
- Iron overload contributes to microglial activation and neurological dysfunction, but mechanisms are unclear.
- N6-methyladenosine (m6A) modification dysregulation is implicated in cellular processes.
Purpose of the Study:
- To elucidate the molecular mechanisms linking arsenic exposure, iron overload, and neuroinflammation.
- To investigate the role of fat mass and obesity-associated protein (FTO) in arsenic-induced neurotoxicity.
- To identify potential therapeutic targets for mitigating arsenic-related neurological damage.
Main Methods:
- Utilized iron chelation therapy in mouse models.
- Investigated arsenic-induced changes in m6A modification levels and FTO expression.
- Employed systemic and microglial-specific Fto knock-in and knock-out mouse models.
- Performed m6A-sequencing to identify modified autophagy-related genes.
- Analyzed human cortical tissues for correlations between arsenic, iron, FTO, ATG9A, and inflammatory factors.
Main Results:
- Iron chelation therapy ameliorated arsenic-induced iron overload and microglial activation via ferritinophagy.
- Arsenic exposure increased m6A modification and decreased FTO levels.
- Fto manipulation in mice altered susceptibility to arsenic-induced microglial activation and neurotoxicity.
- ATG9A was identified as a key m6A-modified gene regulated by FTO in arsenic-induced ferritinophagy.
- Human tissues showed correlations between arsenic levels and markers of inflammation and iron, inversely correlating with FTO.
Conclusions:
- FTO plays a critical role in regulating microglial activation and neuroinflammation in response to arsenic exposure.
- FTO-mediated regulation of ATG9A and ferritinophagy is a key pathway in arsenic neurotoxicity.
- FTO represents a promising therapeutic target for treating arsenic-induced neurotoxicity.
